COUNTERPOINT: Should Radiation Therapy Be Routinely Used in the Adjuvant Treatment of Stage III Endometrial Cancer?

September 18, 2018

The routine use of adjuvant radiation therapy in stage III endometrial cancer patients is not supported by the current literature and should not be employed universally in this group of patients.

No-The Literature Does Not Support Routine Use of Radiation Therapy

Endometrial cancer is the most common gynecologic malignancy. It was estimated that over 61,000 new cases and nearly 11,000 deaths from endometrial cancer occurred in the United States in 2017.[1] Nearly 70% of women diagnosed with endometrial cancer will present with stage I disease limited to the uterus, with a 5-year survival rate of 90%.[2] Approximately 13% of women will be diagnosed with stage III/IV disease, with 5-year survival rates of 60% and 30%, respectively.[3] Pelvic radiation therapy has traditionally been utilized in these cases to improve local control.[4] Previously, endometrial cancer was considered to be a chemoresistant disease; however, it is now known that numerous chemotherapeutic agents, including doxorubicin, carboplatin, and paclitaxel, are active in endometrial cancer.[5] The optimal management of patients with advanced endometrial cancer has yet to be defined, particularly in stage III patients. The primary goal of adjuvant therapy should be to improve patient survival, yet to date, no overall survival (OS) advantage has been associated with the use of radiation therapy in endometrial cancer. The question remains-should adjuvant pelvic radiation therapy be routinely utilized in stage III endometrial cancer?

The Gynecologic Oncology Group (GOG) 122 trial was a randomized controlled trial that compared whole-abdominal radiotherapy vs doxorubicin/cisplatin chemotherapy in patients with stage III/IV endometrial cancer. This trial demonstrated improved progression-free survival and OS for patients treated with chemotherapy.[6] A parallel multicenter randomized controlled trial was performed in Italy, evaluating pelvic radiation therapy vs chemotherapy for high-risk (stages IC to III) endometrial cancer patients. This trial included a significant number (64%) of stage III patients.[7]

The Cochrane Collaboration performed a separate analysis combining these two trials, but only included the stage III endometrial cancer patients (620 patients). Their analysis revealed statistically significant improvement in OS for women with stage III/IV endometrial cancer who received adjuvant chemotherapy compared with adjuvant radiotherapy (hazard ratio [HR], 0.75; 95% CI, 0.57–0.99, I2 = 22%). This survival benefit was evident in a subgroup analysis (514 patients), in which only stage III data were pooled (HR, 0.76; 95% CI, 0.57–1.02; I2 = 9%).[8] The authors concluded that women who received chemotherapy after surgery had approximately a 25% increase in survival time compared with those receiving radiotherapy after surgery.

Despite the OS advantage from chemotherapy alone compared with radiation therapy alone in stage III endometrial cancer, many continue to incorporate radiation therapy in the management of these women due to the increased incidence of pelvic relapse in those patients treated with chemotherapy alone.[6,9] The NRG/GOG 258 trial was a randomized controlled trial evaluating combination chemoradiotherapy vs chemotherapy alone in advanced endometrial cancer. Final results are pending, but the presented abstract demonstrates that, although combined chemoradiotherapy reduced the rate of local recurrence compared with chemotherapy alone, it did not increase recurrence-free survival or OS in optimally debulked stage III/IVA patients.[9] The addition of radiation therapy did not improve survival, and the combined-modality group had a significantly higher rate of distant metastasis compared with the chemotherapy-alone group (28% vs 21%; HR, 1.36; 95% CI, 1.00–1.86).[9]

The randomized controlled PORTEC-3 trial compared adjuvant chemoradiotherapy vs radiotherapy alone in women with high-risk endometrial cancer. Adjuvant chemotherapy given during and after radiotherapy did not improve 5-year OS, although it did increase failure-free survival.[10] Interestingly, the radiotherapy-alone group had a significantly higher pelvic recurrence rate. The 5-year estimate of pelvic recurrence was 4.9% for the chemoradiotherapy group vs 9.2% for the radiotherapy-alone group (P = .026). Both NRG/GOG 258 and PORTEC-3 failed to demonstrate an OS advantage with the combination of radiation therapy and chemotherapy compared with single-modality treatment.

Stage III endometrial cancer patients represent a heterogeneous group with a high risk of disease recurrence. Randomized controlled trials have demonstrated that adjuvant chemotherapy provides an OS advantage compared with radiation therapy. Despite this survival advantage, women who receive adjuvant chemotherapy are at increased risk for local recurrence.[10] As noted, in randomized controlled trials, the combination of radiotherapy and chemotherapy has not translated into a survival advantage compared with single-modality treatment. However, these women can undergo successful salvage therapy if they develop a pelvic recurrence. Creutzberg et al performed an analysis of the PORTEC trial to determine the rates of local control and survival after relapse. The 8-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 15% in the control group (P < .0001).[11] Survival after relapse was significantly better in the patient group without previous radiotherapy. Treatment for vaginal relapse was effective, with an 89% complete response rate and a 65% 5-year survival rate in the control group. While endometrial cancer patients treated with chemotherapy alone in the adjuvant setting remain at risk for pelvic relapse, if these relapses occur, they can be salvaged at the time of recurrence, with excellent results.

When counseling patients on the potential benefits of adjuvant therapy, we must also balance these benefits with their known associated toxicities. Multimodality therapy inherently has increased toxicities compared with single-modality therapy. PORTEC-3 revealed that grade 3 or worse adverse events were reported in 70% of the patients in the chemoradiotherapy group compared with 34% in the radiotherapy-alone group.[12] NRG/GOG 258 demonstrated that the combined-therapy group experienced overall worse quality of life and gastrointestinal toxicity compared with the chemotherapy-alone group.[13] In this trial, 75% of patients in the combined-therapy arm completed the study therapy vs 85% in the chemotherapy-alone arm.[9] These data demonstrate the increased toxicity from multimodality therapy in a setting in which there is no OS benefit. The addition of radiotherapy to chemotherapy also limited the ability of patients to complete the prescribed regimen, possibly due to radiation treatment side effects.

Stage III endometrial cancer presents a treatment dilemma in which the optimal adjuvant therapy has yet to be defined. It is clear that one size does not fit all. These patients are at increased risk for recurrence, particularly distant metastasis. Chemotherapy is the only adjuvant therapy that has proven to have a statistically significant impact on overall survival. The addition of radiotherapy decreases pelvic recurrence-but at the price of increased toxicity and with no OS benefit. If and when these patients experience a local recurrence, salvage therapy has proven to be effective in obtaining a complete response. We must look beyond stage when choosing adjuvant therapy and focus on individual patient risk factors. Peritoneal cytology, although no longer part of the staging process, still provides valuable insight into those patients at increased risk for distant metastasis and those patients who may be best treated with chemotherapy alone.[14] We need to move beyond traditional morphologic risk factors and begin to utilize molecular markers such as POLE mutations, microsatellite instability hypermutations, and other genetic mutations to help identify those patients who would truly benefit from adjuvant therapy, and tailor these therapies to the individual patient. The routine use of adjuvant radiation therapy in stage III endometrial cancer patients is not supported by the current literature and should not be employed universally in this group of patients.

Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30.

2. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri: FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95(suppl 1):S105-S143.

3. Kosary CL. Chapter 15: Cancer of the corpus uteri. In: Gloeckler Ries LA, Young JL, Keel GE, et al (editors). Cancer survival among adults: US SEER program, 1988-2001. Patient and tumor characteristics. Bethesda, MD: National Cancer Institute; 2007. p. 123-32.

4. Schorge JO, Molpus KL, Goodman A, et al. The effect of postsurgical therapy on stage III endometrial carcinoma. Gynecol Oncol. 1996;63:34-9.

5. McMeekin DS. Where is the future of endometrial cancer therapy? Ann Oncol. 2009;20:1757-61.

6. Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:36-44.

7. Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95:266-71.

8. Galaal K, Al Moundhri M, Bryant A, et al. Adjuvant chemotherapy for advanced endometrial cancer. Cochrane Database Syst Rev. 2014:CD010681.

9. Matei D, Filiaci VL, Randall M, et al. A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma. J Clin Oncol. 2017;35(suppl):abstr 5505.

10. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:295-309.

11. Creutzberg CL, van Putten WL, Koper PC, et al. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol Oncol. 2003;89:201-9.

12. de Boer SM, Powell ME, Mileshkin L, et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17:1114-26.

13. Matulonis U, Filiaci V, Huang H, et al. Analysis of patient-reported outcomes (PROs) for GOG-258, a randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel (Cis-RT+CP) vs. carboplatin and paclitaxel (CP) for optimally debulked, locally advanced endometrial carcinoma: A Gynecologic Oncology Group/NRG study. J Clin Oncol. 2018;36(suppl):abstr 5589.

14. Milgrom SA, Kollmeier MA, Abu-Rustum NR, et al. Positive peritoneal cytology is highly predictive of prognosis and relapse patterns in stage III (FIGO 2009) endometrial cancer. Gynecol Oncol. 2013;130:49-53.

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